Intermediates in the preparation of isoxazolyl benzamides

ABSTRACT

Substituted or unsubstituted isoxazolyl benzamides, e.g., o-(3-phenylisoxazol-5-yl)-N-methylbenzamide, are prepared by cyclizing a corresponding 1-hydroxy-1-[substituted or unsubstituted -β-(hydroxyimino)phenethyl]-2-alkyl phthalimidine with a strong acid and are useful as minor tranquilizers, muscle relaxants, and sleep inducers.

This is a division of application Ser. No. 549,934, filed Feb. 14, 1975,now U.S. Pat. No. 3,987,179.

This invention relates to isoxazolyl benzamides which exhibit minortranquilizer, muscle relaxant and sleep inducer activity. Moreparticularly, it relates to substituted or unsubstituted isoxazolylbenzamides, intermediates thereof, and to processes for theirpreparation.

The compounds of this invention may be represented by the followingstructural formula: ##STR1## where R₁ represents hydrogen, halo havingan atomic weight of about 19 to 36, i.e., fluoro or chloro, straightchain lower alkyl, i.e., straight chain alkyl having 1 to 4 carbonatoms, e.g., methyl, ethyl, propyl and the like, straight chain loweralkoxy, i.e., straight chain alkoxy having 1 to 4 carbon atoms, e.g.,methoxy, ethoxy, propoxy and the like, or trifluoromethyl, and

R₂ represents straight chain lower alkyl as defined above.

The compounds of formula (I) are prepared according to the followingreaction scheme: ##STR2## where R₁ and R₂ are as defined above.

The compounds of formula (I) are prepared by cyclizing a compound of theformula (II) with a polyphosphoric acid. Although inert solvents such asdiethyl ether, tetrahydrofuran, dioxane, aliphatic hydrocarbons,aromatic hydrocarbons, or halogenated hydrocarbons can be used, it ispreferred that the reaction be carried out in excess of thepolyphosphoric acid. The temperature of the reaction is not critical,but it is preferred that the reaction be carried out at a temperaturebetween about 80° to 150° C., preferably from about 100° to 110° C. Thereaction may be run from 1 to 6 hours, preferably from about 2 to 4hours. The product is recovered by conventional techniques, e.g.,evaporation and crystallization.

The compounds of formula (II) are prepared according to the followingreaction scheme: ##STR3## where M is an alkali metal, e.g., sodiumpotassium or lithium, and R₁ and R₂ are as defined above.

The compounds of formula (II) are prepared by reacting a compound offormula (III) with a compound of formula (IV) in an inert solvent. Theparticular inert solvent used is not critical, but it is preferred thatthe reaction be carried out in the presence of the ethers, such astetrahydrofuran, dioxane, diethyl ether and the like or the aliphatichydrocarbons such as heptane, hexane and the like, preferablytetrahydrofuran. The temperature of the reaction is not critical, but itis preferred that the reaction be carried out at a temperature betweenabout 0° to 80° C., preferably at room temperature. The reaction may berun from 1 to 12 hours, preferably from about 11/2 to 3 hours. Theresulting adduct of the compounds of formulae (III) and (IV) ishydrolyzed to the compounds of formula (II) using conventionaltechniques, e.g., by use of ammonium chloride solution. The product isrecovered using conventional techniques, e.g., evaporation andrecrystallization.

It is to be noted that the compounds of formula (II) also exist in thefollowing tautomeric forms and said tautomeric forms are also includedwithin this invention. ##STR4##

Many of the compounds of formulae (III) and (IV) are known and may beprepared by methods described in the literature. The compounds offormulae (III) and (IV) not specifically disclosed may be prepared byanalogous methods from known starting materials.

The compounds of formula (I) are useful because they possesspharmacological activity. In particular, the compounds are useful ascentral nervous system depressants, especially as sleep inducers, minortranquilizers, and muscle relaxants as indicated by (1) their ability toproduce docility in behavior tests in mice given 25 to 200 mg/kg ofanimal body weight, i.p. of the test compound according to the 30-wordadjective check sheet system basically as described by Irwin S. Gordon(Research Conference, Medicinal Chemistry, 1959) and Chen (Symposium onSedative and Hypnotic Drugs, Williams and Wilkins, 1954); (2) by theirability to antagonize chronic convulsions and death in mice given 33 to125 mg/kg i.p. of the test compound followed by 50 mg/kg i.p. ofN-sulfamoylazepine; (3) by the hexobarbital reinduction method ofWinter, (J. Pharmacol and Exp. Therap., 94, 7-11, 1948) in which thereinduction of anesthesia after recovery from hexobarbital inducedanesthesia is used to determine sedative-hypnotic activity in mice given70 mg/kg of animal body weight, i.p. of hexobarbital followedimmediately after the mice regain their righting reflexes by 25 to 200mg/kg of animal body weight, i.p. of the test compound; (4) as indicatedin Cebus monkey using chlonically implanted electrodes. Brain readingsare obtained via a ten or sixteen channel electroencephalograph. For therecording sessions, the monkeys are restrained by neck and waist platesin chairs in full side observation cages at the same time every nightfor 131/2 hours Monday through Thursday. Gross behavior is monitored viaclosed circuit television and video tape recordings. The compounds offormula (I) are administered p.o. at a dosage of from about 1.8 to about30 mg/kg immediately on placing the monkey in the observation cages withat least seven days intervening between drug administration.Physiological saline is administered via a similar route and at the sametime on all control runs. Control data are collected at least 3 days perweek and accumulated to give control date for 15 sessions per monkey.Data from each session are statistically compared via computer analysisto the previous 5-15 control sessions for the particular animal, withparticular emphasis given to the following phases of thesleep-wakefulness cycle: resting awake, light sleep, deep sleep,paradoxical (REM) sleep, "pseudo-"paradoxical sleep, latency to onset ofdeep sleep, and latency to onset of first epoch of paradoxical sleep;(5) as indicated in the cat given typically 5 to 30 mg/kg of animal bodyweight of the active material and tested in sleep studies using chroniccortical and subcortical electrode placements, with eye movementmeasured via electro-oculogram. Brain readings are obtained via GrossModel 6 electroencephalograph, and the gross behavior of the animal ismonitored via closed circuit television and video tape recordings; and(6) by scoring for loss of righting reflex according to the method ofReed-Muench (American Journal of Hygiene, 27:493-497, 1938) in whichmice are administered 12.5 L mg/kg i.p. thioridazine, immediately afterwhich test compound is administered at dosages of 5 to 100 mg/kg in avolumne of 0.1 ml/10 g. body weight. Thirty minutes after dosing, themice are scored for loss of righting reflex.

For such usage, the compounds may be administered orally or parenterallyas such or admixed with conventional pharmaceutical carriers.

The dosage of active ingredient employed for minor tranquilizer andmuscle relaxant use may vary depending on the severity of the conditionbeing treated. However, in general, satisfactory results are obtainedwhen a compound of formula (I) is administered at a daily dosage of fromabout 1 milligram to about 200 milligrams per kilogram of animal bodyweight p.o., preferably given in divided doses 2 to 4 times a day, or insustained release form. For most larger mammals (e.g., primates), thetotal daily dosage is from about 60 milligrams to about 1500 milligrams.Dosage forms suitable for internal use comprise from about 15 to about750 milligrams of active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier or diluent.

The dosage of active ingredient employed for sleep inducer use may varydepending on the severity of the condition being treated. However, ingeneral, satisfactory results are obtained when a compound of theformula (I) is administered at a daily dosage of from about 2 milligramsto about 150 milligrams per kilogram of animal body weight p.o.,typically given in a single dose at bedtime. For most larger mammals,the total daily dosage is from about 150 milligrams to about 1500milligrams, preferably at bedtime in a single dose, and dosage formssuitable for internal administration comprise from about 35 to about 750milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent. The preferred pharmaceuticalcompositions from the standpoint of preparation and ease ofadministration are solid compositions, particularly hardfilled capsulesand tablets.

EXAMPLE 1 1-Hydroxy-1-[β-(hydroxyimino)phenethyl]-2-methylphthalimidine

A solution of 5.4 g. (0.04 mole) acetophenone oxime in 90 ml.tetrahydrofuran is cooled to 0° C and there is added dropwise 55 ml.n-butyllithium in hexane (0.088 mole) with the temperature not exceeding+5° C during the addition. After the addition is complete, the mixtureis stirred for 21/2 hours at 0° C and then warmed to room temperature,and there is added dropwise a solution of 7.08 g. (0.044 mole) N-methylphthalimide in 85 ml. tetrahydrofuran. After the addition is complete,the mixture is stirred for 11/2 hours at room temperature, then cooledto 0° C and quenched by the addition of saturated ammonium chloride. Thelayers are separated and the organic phase is washed with ammoniumchloride solution, dried and evaporated in vacuo. The solid residue istriturated with ether, filtered and recrystallized from ethyl acetate togive 1-hydroxy-1-[β-(hydroxyimino)phenethyl]-2-methylphthalimidine, m.p.142.5°-143.5° C.

Following the above procedure and using in place of acetophenone oximean equivalent amount of

(a) p-chloroacetophenone oxime,

(b) p-methylacetophenone oxime,

(c) p-methoxyacetophenone oxime, or

(d) m-trifluoromethylacetophenone oxime,

there is obtained

(a)1-hydroxy-1-[4-chloro-β-(hydroxyimino)phenethyl]-2-methylphthalimidine,

(b)1-hydroxy-1-[4-methyl-β-(hydroxyimino)phenethyl]-2-methylphthalimidine,

(c)1-hydroxy-1-[4-methoxy-β-(hydroxyimino)phenethyl]-2-methylphthalimidine,or

(d)1-hydroxy-1-[3-trifluoromethyl-β-(hydroxyimino)phenethyl]-2-methylphthalimidine,respectively.

EXAMPLE 2 o-(3-phenylisoxazol-5-yl)-N-methyl benzamide

A mixture of 55 g. (0.186 mole)1-hydroxy-1-[β-(hydroxyimino)phenethyl]-2-methylphthalimidine and 550grams of polyphosphoric acid is heated at 100° C. for 2 hrs. The mixtureis poured onto ice and extracted with methylene cloride. The methylenechloride is washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue is crystallized from ether/methylenechloride and recrystallized from benzene to giveo-(3-phenylisoxazol-5-yl)-N-methyl benzamide, m.p. 119°-121° C.

Following the above procedure and using in place of1-hydroxy-1-[β-(hydroxyimino)phenethyl]-2-methylphthalimidine, anequivalent amount of

(a)1-hydroxy-1-[p-chloro-β-(hydroxyimino)phenethyl]-2-methylphthalimidine,

(b)1-hydroxy-1-[p-methyl-β-(hydroxyimino)phenethyl]-2-methylphthalimidine,

(c)1-hydroxy-1-[p-methoxy-β-(hydroxyimino)phenethyl]-2-methylphthalimidine,or

(d)1-hydroxy-1-[m-trifluoromethyl-β-(hydroxyimino)phenethyl-2-methylphthalimidine,

there is obtained

(a) o-(3-p-chlorophenylisoxazol-5-yl)-N-methyl benzamide,

(b) o-(3-p-tolylisoxazol-5-yl)-N-methyl benzamide,

(c) o-(3-p-methoxyphenylisoxazol-5-yl)-N-methyl benzamide, or

(d) o-(3-m-trifluoromethylphenylisoxazol-5-yl)-N-methyl benzamide,respectively.

The o-(3-phenylisoxazol-5-yl)-N-methyl benzamide of this example is aneffective sleep inducer when orally administered to an animal in need ofsaid treatment at a dosage of 200 mg. just before bedtime. Theo-(3-phenylisoxazol-5-yl)-N-methyl benzamide of this example is also aneffective minor tranquilizer and muscle relaxant when orallyadministered to an animal in need of said treatment at a dosage of 100mg. 2 to 4 times per day.

What is claimed is:
 1. A compound of the formula ##STR5## where R₁represents hydrogen, halo having an atomic weight of about 19 to 36,straight chain lower alkyl having 1 to 4 carbon atoms, straight chainlower alkoxy having 1 to 4 carbon atoms, or trifluoromethyl, andR₂represents straight chain lower alkyl.